dbSNP rs77883212: KCNK12:p.Ile284Ile (chr2-47521348-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_022055.2(KCNK12):c.852C>T(p.Ile284Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0021 in 1,613,718 control chromosomes in the GnomAD database, including 66 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 39 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 27 hom. )

Consequence

KCNK12
NM_022055.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.03

Publications

1 publications found

Variant links:

Genes affected

KCNK12 (HGNC:6274): (potassium two pore domain channel subfamily K member 12) This gene encodes one of the members of the superfamily of potassium channel proteins containing two pore-forming P domains. The product of this gene has not been shown to be a functional channel, however, it may require other non-pore-forming proteins for activity. [provided by RefSeq, Jul 2008]

KCNK12 links:

MSH2 (HGNC:7325): (mutS homolog 2) This locus is frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). When cloned, it was discovered to be a human homolog of the E. coli mismatch repair gene mutS, consistent with the characteristic alterations in microsatellite sequences (RER+ phenotype) found in HNPCC. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

MSH2 Gene-Disease associations (from GenCC):

Lynch syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet, G2P
Lynch syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
Muir-Torre syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
mismatch repair cancer syndrome 1
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
mismatch repair cancer syndrome 2
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
ovarian cancer
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
malignant pancreatic neoplasm
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
prostate cancer
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
rhabdomyosarcoma
Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
breast cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
hereditary breast carcinoma
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

MSH2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.51).

BP6

Variant 2-47521348-G-A is Benign according to our data. Variant chr2-47521348-G-A is described in ClinVar as Benign. ClinVar VariationId is 791853.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.03 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0109 (1660/152302) while in subpopulation AFR AF = 0.038 (1579/41572). AF 95% confidence interval is 0.0364. There are 39 homozygotes in GnomAd4. There are 766 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1660 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022055.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KCNK12	NM_022055.2	MANE Select	c.852C>T	p.Ile284Ile	synonymous	Exon 2 of 2	NP_071338.1	Q9HB15
MSH2	NM_001406674.1		c.2752+8928G>A		intron	N/A	NP_001393603.1
MSH2	NM_001406631.1		c.2752+8928G>A		intron	N/A	NP_001393560.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KCNK12	ENST00000327876.5	TSL:1 MANE Select	c.852C>T	p.Ile284Ile	synonymous	Exon 2 of 2	ENSP00000327611.3	Q9HB15
MSH2	ENST00000645506.1		c.2752+8928G>A		intron	N/A	ENSP00000495455.1	A0A2R8Y6P0
MSH2	ENST00000644092.1		n.*1052+8928G>A		intron	N/A	ENSP00000496351.1	A0A2R8Y7S8

Frequencies

GnomAD3 genomes

AF:

0.0109

AC:

1655

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0380

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00380

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00669

GnomAD2 exomes

AF:

0.00285

AC:

709

AN:

249108

AF XY:

0.00213

show subpopulations

Gnomad AFR exome

AF:

0.0394

Gnomad AMR exome

AF:

0.00160

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000890

Gnomad OTH exome

AF:

0.00132

GnomAD4 exome

AF:

0.00119

AC:

1735

AN:

1461416

Hom.:

Cov.:

AF XY:

0.00101

AC XY:

734

AN XY:

726956

show subpopulations

African (AFR)

AF:

0.0437

AC:

1462

AN:

33468

American (AMR)

AF:

0.00168

AC:

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39688

South Asian (SAS)

AF:

0.000163

AC:

AN:

86116

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53302

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000288

AC:

AN:

1111874

Other (OTH)

AF:

0.00242

AC:

146

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

191

286

382

477

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

150

200

250

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0109

AC:

1660

AN:

152302

Hom.:

Cov.:

AF XY:

0.0103

AC XY:

766

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.0380

AC:

1579

AN:

41572

American (AMR)

AF:

0.00379

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000580

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68022

Other (OTH)

AF:

0.00662

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

176

265

353

441

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00388

Hom.:

Bravo

AF:

0.0126

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Benign

0.94

PhyloP100

2.0

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over